Post-translational control of mitochondria by Fbxo7 in Parkinson's disease

Parkinson’s disease is a progressive, neurodegenerative disorder which is characterised by the loss of dopaminergic neurons within the substantia nigra. At a cellular level, mitochondrial dysfunction, oxidative stress and proteasomal dysfunction are all implicated in the pathogenesis of the disease. The majority of PD cases are late onset and arise sporadically, with age being the primary risk factor. Approximately 5-10% of cases however are early onset, occurring in individuals under the age of 50. These early forms of PD are typically caused by mutations in one or more Parkinson’s-related genes. In 2008, mutations in the gene FBXO7 were identified as causing early-onset Parkinsonian pyramidal syndrome. Fbxo7’s canonical function is as the substrate recruiting domain of an E3 SCF ubiquitin ligase complex. Mitochondrial defects have previously been detected in cells lacking Fbxo7 expression, although the precise mechanisms through which Fbxo7 protects cells from mitochondrial dysfunction and neuronal cell death are not currently fully understood. In this thesis I characterised two patient fibroblast cell lines with novel mutations in FBXO7. A leucine to proline mutation at amino acid 250 was found to be destabilising and to disrupt the interaction between Fbxo7 and its binding partner PI31. Fibroblasts carrying this mutation were also found to have reduced levels of mitochondrial respiration, increased ROS and increased sensitivity to oxidative and proteasomal stress. Fibroblasts with an N-terminal truncating S93X mutation were also found to have higher levels of ROS, increased mitochondrial fragmentation and increased mitochondrial membrane depolarisation, indicative of elevated mitochondrial dysfunction. In addition, I validated the mitochondrial fission adaptors MiD49 and MiD51 as novel binding partners of Fbxo7. MiD49 and MiD51 protein levels were found to be stabilised in the presence of Fbxo7, independently of Fbxo7’s activity as part of an SCF ligase complex. MiD49 and MiD51 were also found to interact with PI31 with initial evidence suggesting that PI31 may compete with the fission adaptors for binding to Fbxo7 through the ligase’s FP domain. Overall, in this thesis I provide further evidence for the role of Fbxo7 in the development of PPS and describe a novel mitochondrial function for Fbxo7 in the stabilisation of the fission adaptors MiD49 and MiD51.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Simpson, Lorna

Advisor dc:contributor.advisor

• Laman, Heike

• Fbxo7
• mitochondria
• Parkinson's disease

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e620f988-ef85-4447-9d21-2f5afcb4050c/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.101924

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/358101